This application discloses a method of treating or preventing atrial arrhythmias which utilizes compounds which are blockers of the ultra-rapidly-activating delayed rectifier K.sup.+ current (I.sub.Kur) of the human atrium in a use-dependent and/or rate-dependent manner, and which preferentially block at fast heart rates so that the effect is realized or maximized when required.
Atrial flutter and/or atrial fibrillation (AF) are the most commonly sustained cardiac arrhythmias in clinical practice and are likely to increase in prevalence with the aging of the population. Currently, AF affects more than 1 million Americans annually, represents over 5% of all admissions for cardiovascular diseases and causes more than 80,000 strokes each year in the United States. While AF is rarely a lethal arrhythmia, it is responsible for substantial morbidity and can lead to complications such as the development of congestive heart failure or thromboembolism. Currently available Class I and Class III antiarrhythmic drugs reduce the rate of recurrence of AF, but are of limited use because of a variety of potentially adverse effects including ventricular proarrhythmia. Because current therapy is inadequate and fraught with side effects, there is a clear need to develop new therapeutic approaches.
Although various antiarrythmic agents are now available on the market, those having both satisfactory efficacy and a high margin of safety have not been obtained. For example, antiarrhythmic agents of Class I, according to the classification scheme of Vaughan-Williams ("Classification of antiarrhythmic drugs", Cardiac Arrhythmias, edited by: E. Sandoe, E. Flensted-Jensen, K. Olesen; Sweden, Astra, Sodertalje, pp 449-472, 1981) which cause a selective inhibition of the maximum velocity of the upstroke of the action potential (V.sub.max) are inadequate for preventing ventricular fibrillation. In addition, they have problems regarding safety, namely, they cause a depression of myocardial contractility and have a tendency to induce arrhythmias due to an inhibition of impulse conduction. .beta.-adrenergenic receptor blockers and calcium channel (I.sub.Ca) antagonists which belong to Class II and IV, respectively, have a defect in that their effects are either limited to a certain type of arrhythmia or are contraindicated because of their cardiac depressant properties in certain patients with cardiovascular disease. Their safety, however, is higher than that of the antiarrhythmic agents of Class I.
Antiarrhythmic agents of Class III are drugs that cause a selective prolongation of the action potential duration (APD) without a significant depression of the maximum upstroke velocity (V.sub.max). Available drugs in this class are limited in number. Examples such as sotalol and amiodarone have been shown to possess interesting Class III properties (Singh B. N., Vaughan Williams E. M., "A third class of anti-arrhythmic action: effects on atrial and ventricular intracellular potentials and other pharmacological actions on cardiac muscle of MJ 1999 and AH 3747", Br. J. Pharmacol 1970; 39:675-689, and Singh B. N., Vaughan Williams E. M., "The effect of amiodarone, a new anti-anginal drug, on cardiac muscle", Br. J. Pharmacol 1970; 39:657-667), but these are not selective Class III agents. Sotalol also possesses Class II (.beta.-adrenergic blocking) effects which may cause cardiac depression and is contraindicated in certain susceptible patients. Amiodarone also is not a selective Class III antiarrhythmic agent because it possesses multiple electrophysiological actions and is severely limited by side effects (Nademanee, K., "The Amiodarone Odessey", J. Am. Coll. Cardiol. 1992; 20:1063-1065.) Drugs of this class are expected to be effective in preventing ventricular fibrillation. Selective Class III agents, by definition, are not considered to cause myocardial depression or an induction of arrhythmias due to inhibition of conduction of the action potential as seen with Class I antiarrhythmic agents.
Class III agents increase myocardial refractoriness via a prolongation of cardiac action potential duration (APD). Theoretically, prolongation of the cardiac action potential can be achieved by enhancing inward currents (i.e. Na.sup.+ or Ca.sup.2+ currents; hereinafter I.sub.Na and I.sub.Ca, respectively) or by reducing outward repolarizing potassium K.sup.+ currents. The delayed rectifier (I.sub.K) K.sup.+ current is the main outward current involved in the overall repolarization process during the action potential plateau, whereas the transient outward (I.sub.to) and inward rectifier (I.sub.K1) K.sup.+ currents are responsible for the rapid initial and terminal phases of repolarization, respectively. Cellular electrophysiologic studies have demonstrated that I.sub.K consists of two pharmacologically and kinetically distinct K.sup.+ current subtypes, I.sub.Kr (rapidly activating and deactivating) and I.sub.Ks (slowly activating and deactivating). (Sanguinetti and Jurkiewicz, "Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by Class III antiarrhythmic agents", J Gen Physiol 1990, 96:195-215).
Class III antiarrhythmic agents currently in development, including d-sotalol, dofetilide (UK-68,798), almokalant (H234/09), E-4031 and methanesulfonamide--N--[1'-6-cyano-1,2,3,4-tetrahydro-2-naphthalenyl)-3,4- dihydro-4-hydroxyspiro[2H-1-benzopyran-2,4'-piperidin]-6yl], (+)-, monochloride (MK-499) predominantly, if not exclusively, block I.sub.Kr. Although, amiodarone is a blocker of I.sub.Ks (Balser J. R. Bennett, P. B., Hondeghem, L. M. and Roden, D. M. "Suppression of time-dependent outward current in guinea pig ventricular myocytes: Actions of quinidine and amiodarone", Circ. Res. 1991, 69:519-529), it also blocks I.sub.Na and I.sub.Ca, effects thyroid function, is as a nonspecific adrenergic blocker, and acts as an inhibitor of the enzyme phospholipase (Nademanee, K. "The Amiodarone Odessey". J. Am. Coll. Cardiol. 1992; 20:1063-1065). Therefore, its method of treating arrhythmia is uncertain.
Reentrant excitation (reentry) has been shown to be a prominent mechanism underlying supraventricular arrhythmias in man. Reentrant excitation requires a critical balance between slow conduction velocity and sufficiently brief refractory periods to allow for the initiation and maintenance of multiple reentry circuits to coexist simultaneously and sustain AF. Increasing myocardial refractoriness by prolonging APD, prevents and/or terminates reentrant arrhythmias. Most selective, Class III antiarrhythmic agents currently in development, such as d-sotalol and dofetilide predominantly, if not exclusively, block I.sub.Kr, the rapidly activating component of I.sub.K found both in atrium and ventricle in man.
Since these I.sub.Kr blockers increase APD and refractoriness both in atria and ventricle without affecting conduction per se, theoretically they represent potential useful agents for the treatment of arrhythmias like AF. These agents have a liability in that they have an enhanced risk of proarrhythmia at slow heart rates. For example, torsades de pointes, a specific type of polymorphic ventricular tachycardia which is commonly associated with excessive prolongation of the electrocardigraphic QT interval, hence termed "acquired long QT syndrome", has been observed when these compounds are utilized (Roden, D. M. "Current Status of Class III Antiarrhythmic Drug Therapy", Am J. Cardiol, 1993; 72:44B-49B). This exaggerated effect at slow heart rates has been termed "reverse frequency-dependence" and is in contrast to frequency-independent or frequency-dependent actions. (Hondeghem, L. M., "Development of Class III Antiarrhythmic Agents", J. Cardiovasc. Cardiol. 20 (Suppl. 2):S17-S22).
The slowly activating component of the delayed rectifier (I.sub.Ks) potentially overcomes some of the limitations of I.sub.Kr blockers associated with ventricular arrhythmias. Because of its slow activation kinetics however, the role of I.sub.Ks in atrial repolarization may be limited due to the relatively short APD of the atrium. Consequently, although I.sub.Ks blockers may provide distinct advantage in the case of ventricular arrhythmias, their ability to affect supra-ventricular tachyarrhythmias (SVT) is considered to be minimal.
Another major defect or limitation of most currently available Class III antiarrhythmic agents is that their effect increases or becomes more manifest at or during bradycardia or slow heart rates, and this contributes to their potential for proarrhythmia. On the other hand, during tachycardia or the conditions for which these agents or drugs are intended and most needed, they lose most of their effect. This loss or diminishment of effect at fast heart rates has been termed "reverse use-dependence" (Hondeghem and Snyders, "Class III antiarrhythmic agents have a lot of potential but a long way to go: Reduced effectiveness and dangers of reverse use dependence", Circulation (1990),81:686-690; Sadanaga et al ., "Clinical evaluation of the use-dependent QRS prolongation and the reverse use-dependent QT prolongation of class III antiarrhythmic agents and their value in predicting efficacy" Amer Heart Journal (1993)126: 114-121), or "reverse rate-dependence" (Bretano, "Rate dependence of class III actions in the heart", Fundam Clin Pharmacol (1993) 7:51-59; Jurkiewicz and Sanguinetti, "Rate-dependent prolongation of cardiac action potentials by a methanesulfonanilide class III antiarrhythmic agent: Specific block of rapidly activating delayed rectifier K+current by dofetilide", Circ Res (1993) 72:75-83). Thus, an agent that has a use-dependent or rate-dependent profile, opposite that possessed by most current class III antiarrhythmic agents, should provide not only improved safety but also enhanced efficacy.
In intact human atrial myocytes, an ultra-rapidly activating delayed rectifier K.sup.+ current, (I.sub.Kur), which is also known as the sustained outward current, I.sub.sus or I.sub.so, has been identified. This current has properties and kinetics identical to those expressed by the human K.sup.+ channel clone (hKv1.5, HK2) when isolated from the human heart and stably expressed in human (HEK-293) cell lines. (Wang et al., "Sustained depolarization-induced outward current in human atrial myocytes. Evidence for a novel delayed rectifier K+ current similar to Kv1.5 cloned channel currents", Circ. Res. 1993; 73:1061-1076; Fedida et al., "Identity of a novel delayed rectifier current from human heart with a cloned K+ channel current", Circ. Res. 1993, 73:210-216; Snyders et al., "A rapidly activating and slowly inactivating potassium channel cloned from human heart. Functional analysis after stable mammalian cell culture expression", J. Gen. Physiol. 1993,101:513-543) and originally cloned from rat brain (Swanson et al., "Cloning and Expression of cDNA and genomic clones encoding three delayed rectifier potassium channels in rat brain", Neuron 1990, 4:929-939).
The ultra-rapidly activating delayed rectifier K.sup.+ current (I.sub.Kur) is believed to represent the native counterpart to a cloned potassium channel designated Kv1.5 and, while present in human atrium, it appears to be absent in human ventricle. Furthermore, because of its rapidity of activation and limited slow inactivation, I.sub.Kur is believed to contribute significantly to repolarization in human atrium. Consequently, a specific blocker of I.sub.Kur, that is a compound which blocks I.sub.Kur but has little or no effect on the other K.sup.+ channels of the heart, would overcome the short-comings and disadvantages of other currently used or developed agents. By retarding repolarization and prolonging refractoriness selectively in the human atrium without causing the delays in ventricular repolarization, a selective I.sub.Kur blocker would not produce arrhythmogenic after depolarizations and acquired long QT syndrome observed during treatment with current Class III drugs.
The method of treatment of atrial arrhythmia presented herein provides for greater safety and efficacy as well preferentially providing treatment at fast heart rates when treatment of this type is most desired through "use-dependent" and/or "rate-dependent" block of I.sub.Kur.